Ep.363: Prof. Mauro Maccorrone, Università Campus Bio-Medico di Roma

Ep.363: Prof. Mauro Maccorrone, Università Campus Bio-Medico di Roma

Prof. Mauro Maccarrone joins us and shares his decades-long history in cannabis research. “The first paper was, in fact, published in 1997. And since then, as a biochemist for education, I could contribute, over the years, a few methods to measure metabolic enzymes and also some receptor activity. And year by year, I did consolidate this biochemical side of the story within the endocannabinoid field, and I could apply it to different medical problems through collaborations with clinicians. And we happened to show quite some interesting things over the years in two major sectors. One is reproductive events, human reproductive events. The other one is in neurodegeneration.”

Transcript:

Mauro M.: I'm Mauro Marricone. I'm full professor and Chair of Biochemistry and Molecular Biology at the University of Rome Campus Bio-Medico.

Seth Adler: Immediately, I hear that there is no mention of cannabis anywhere when you introduce yourself.

Mauro M.: Yeah.

Seth Adler: We are here at Cannaan, which is the first medical conference, medical cannabis conference that has been put on by a government, and it happens to be the Israeli government, as we are here in Tel Aviv, which we will get to, but just if you could, give us your history as far as finding cannabis from your roots, so to speak.

Mauro M.: Yeah. Well, my personal journey through endocannabinoids that are actually the only type of active compounds that I've been actively working on, so the endogenous compounds, started a couple of years after the discovery of 2-arachidonoylglycerol by Raphael Mechoulam.

Seth Adler: 2-AG.

Mauro M.: 2-AG. My first paper was, in fact, published in 1997. And since then, as a biochemist for education, I could contribute, over the years, a few methods to measure metabolic enzymes and also some receptor activity. And year by year, I did consolidate this biochemical side of the story within the endocannabinoid field, and I could apply it to different medical problems through collaborations with clinicians. And we happened to show quite some interesting things over the years in two major sectors. One is reproductive events, human reproductive events. The other one is in neurodegeneration.

Mauro M.: I'm Mauro Marricone. I'm full professor and Chair of Biochemistry and Molecular Biology at the University of Rome Campus Bio-Medico.

Seth Adler: Immediately, I hear that there is no mention of cannabis anywhere when you introduce yourself.

Mauro M.: Yeah.

Seth Adler: We are here at Cannaan, which is the first medical conference, medical cannabis conference that has been put on by a government, and it happens to be the Israeli government, as we are here in Tel Aviv, which we will get to, but just if you could, give us your history as far as finding cannabis from your roots, so to speak.

Mauro M.: Yeah. Well, my personal journey through endocannabinoids that are actually the only type of active compounds that I've been actively working on, so the endogenous compounds, started a couple of years after the discovery of 2-arachidonoylglycerol by Raphael Mechoulam.

Seth Adler: 2-AG.

Mauro M.: 2-AG. My first paper was, in fact, published in 1997. And since then, as a biochemist for education, I could contribute, over the years, a few methods to measure metabolic enzymes and also some receptor activity. And year by year, I did consolidate this biochemical side of the story within the endocannabinoid field, and I could apply it to different medical problems through collaborations with clinicians. And we happened to show quite some interesting things over the years in two major sectors. One is reproductive events, human reproductive events. The other one is in neurodegeneration.

Seth Adler: Okay, and so we will get to ... and, basically, that's the beginning and the end, so to speak, so we will get to each of those things a little bit later on. Now let's get back to the conference at hand. We are here. There was a fair amount of representation from the research community. There was a fair amount of representation from the government of Israel itself and some folks in between, if you will. Right?

Mauro M.: Right.

Seth Adler: Regulators and such. Understanding that that was the audience, understanding that this is really the kind of the first of its kind, you said a couple of times that the state of Israel will be a lab in and of itself for legal cannabis, for legal medicinal cannabis, for legal medical-grade cannabis. It depends who you talk to. What do you mean by that?

Mauro M.: I really experienced, on my own skin, how relevant it is to bridge basic science to medical science because, indeed, I did collaborate with clinicians to reach a good level and a good quality of results with an impact on our public health, so I know very well how difficult it is to bridge these two worlds together. What I noticed in this conference, so I'm so glad that they could participate in it, is that they could add on top basic science and medical science, also the other expertises that you need to really face the problem and the complexity a cannabinoid, an endocannabinoid signaling, which is the agriculture part and the economical and communication part.

Mauro M.: So here, I have the feeling that they really wanted to go for it at a most ambitious level, and that all official representatives of the different ministries had the role of "We're in person here," showing that the country really wants to do it in the proper way. Now, nobody else has the possibility or was willing to do that so far, so I think that Israel will show how you should do this type of investigations, putting together all the main players. And if they can make it, as I would anticipate, they would be an example for the rest of the world.

Seth Adler: Absolutely. The only other real option, with respect to Uruguay, as Raquel, who we know from the past, mentioned, with respect to them. The only other real example is Canada. And Canada Health is not necessarily really happy to put their foot forward as far as cannabis is concerned. The government almost begrudgingly -- and with all due respect to Justin Trudeau -- the government as we see, now, with the legislature, begrudgingly doing this, as far as legal cannabis. As far as even the medicinal program. Kind of heavy lifting, slow going. Not the government full-throatedly getting behind it, as you say.

Mauro M.: Yeah, yeah. I can say you're right. That also Canada is very, very advanced in this. But maybe Israel has the very big advantage of the size and an easy way of communicating among their partners. So if they want to do something, and they understand that it's important to go right or left-

Seth Adler: Yeah.

Mauro M.: ... they do the day after.

Seth Adler: That's it.

Mauro M.: Other countries are not really in that position.

Seth Adler: A little bit more phones to call. A little bit more hands to shake, so to speak. Okay, so that's basically an update from Earth. You also have otherworldly updates for us. So this is really unbelievable.

Mauro M.: Well, let's say it's a little bit peculiar, because you know, due to my involvement in understanding the molecular mechanisms of our endogenous system, why is it so important for maintaining homeostases or correcting possible pathologies, we face a specific problem that these [inaudible 00:07:53] in this conference related to bone metabolism, which is a major problem on earth, and we know how osteoporosis impacts on the elderly everywhere in the world. But we had the special opportunity to check the role of endocannabinoids in osteoporosis in microgravity. So a special condition that you can have out of Earth, on the International Space Station, where osteoporosis is a problem, major problem, and a fast problem that the astronauts had to face, because of the loss of load, the work on the muscles. Bones get weaker, and you have an osteoporosis-like event there. So we could make a proposal that was selected by the Italian Space Agency, ASI, the European Space Agency, and the American Space Agency, NASA, and it was flown to the space station last August.

Seth Adler: Unbelievable.

Mauro M.: And we are now working, analyzing the data that we got back from the astronauts.

Seth Adler: Well, what did they do? How did they do it so that we understand what happened out there?

Mauro M.: Yeah, well, I have to be brief, but hopefully, I can give you the sense of the experiment.

Seth Adler: Fair enough.

Mauro M.: We found out, on Earth, that some of our blood cells are able to be reprogrammed, if you instruct them in the proper way. And they can be able to make bones. What they called osteoblasts. So cells able to make bone.

Seth Adler: To make bone.

Mauro M.: Bones, yes. so what we propose is to, and we actually did, is to take blood from a donor, in the case it was actually myself-

Seth Adler: Oh my God.

Mauro M.: ... and you reinstruct them in the lab, and then you send them with the astronaut in space. When space conditions are around you, so they're in microgravity, you inject a certain activator, and if the hypothesis is correct, cells will become making bones. They will become osteoblasts. If this is true, there is a great advantage in using your own blood with an auto-transfusion after that. You get back your blood, but your blood will now help you to make bones and compensate the loss of bones due to the special environment. And the double-advantage is that, if that works in space, it should work, also now, on Earth, and could become a -- I would not say a alternative for -- but an additional way of correcting osteoporosis, besides a number of medicine drugs that are available, and that are often a little bit heavy for the patients.

Seth Adler: I see. And this is some of the delicate language, by the way, that you use. I hope to have enough time to talk to you about that, when you speak of other medications. Okay, so this brings us back to Earth, so to speak. And I find it remarkable that, whether or not you've been to space, part of you has, right?

Mauro M.: Oh, yeah, right, yeah.

Seth Adler: So, in some respects, Mauro's been-

Mauro M.: I've been there.

Seth Adler: Yeah, you've been there. In your presentation, you brought up osteoporosis. And you brought up the difference between a Mediterranean -- and I think it was women, specifically -- versus kind of everybody else. And the thinking was is that the oil is it? The diet? What is it? And just take us through, a little bit, of your learnings as far as osteoporosis and the endocannabinoid system.

Mauro M.: Well, you know, osteoporosis, as we were saying, is a major problem. Actually, it's not even a pathology. It's a known diseased state. It's normal. And, for some reason, may be strongly related to hormones, sex hormones. It is more common in women than in men. I would not be too surprised, because if we see how the major metabolic enzymes of the endocannabinoids are regulated, we find out that one of them, that breaks them down, and that, in real life, is the major controller of the end of the level of endocannabinoids, has a place where estrogen, the relevant female hormone, acts to activate that molecule. So there is a cross-talk between sex hormones, and endocannabinoids. And after all, they are both lipids, and anyway, they should go hand-in-hand.

Mauro M.: So it is possible that, by this gene expression, regulation of the levels of the molecule that control endocannabinoids by sex hormones, the two systems talk to each other, and even for bone remodeling, this is relevant.

Seth Adler: Okay. And so that's for everyone. Why the distinction in the Mediterranean?

Mauro M.: There we could have a different layer of complexity, whereby the diet, introducing a number of anti-oxidants and fatty acids of a particular quality -- you know that olive oil is one of the most relevant ingredients -- may change the way that we elaborate our endogenous lipids. And so, although the molecular clues there are not yet clear, you can expect that an influence can be found.

Seth Adler: Yeah, and my takeaway from that, please correct me, was that the endocannabinoid system in the folks from the Mediterranean was healthier than their compatriots from the rest of the world.

Mauro M.: I don't think that we can state that yet. But we can say that, depending on what you eat, the endocannabinoid signaling changes. Someone reported that, if you have more of what are called omega-three fatty acids, you have a better signaling for a certain process at least. But that does not immediately mean the Mediterranean diet for the olive oil, may mean eating more fish. Which is, again, Mediterranean, but not all the Mediterranean. But healthy food could help your endogenous signals to work better.

Seth Adler: Not just these, yes. So, I want to dive in on the rest of your work. But I want to, it's kind of clunky, but we did talk about 2AG, and I want to talk about FAAH, right? So F-A-A-H.

Mauro M.: You're right.

Seth Adler: Okay, so you're better at explaining this than I am, sir.

Mauro M.: So, this is a little machine -- we call it protein or enzyme -- able to break other entities, and in the specific case, is the enzyme, the more relevant enzyme, for breaking down endocannabinoids. And it is so important, again, in real life, that many, many companies are trying to develop inhibitors of this enzyme, with the aim of keeping high the levels of endocannabinoids in our body. If you wish, instead of getting phytocannabinoids from the plants, someone believes that if you keep your own endogenous compounds high enough, you might correct the number of pathological conditions. The point is that, it is not trivial to qualify an inhibitor. And in a recent case, it happened that someone proposed, stated that the certain molecule was an inhibitor, and this molecule killed some patients. It turned out, and we had to work harder to show that sooner. We took just one year to complete quite a complex study.

Mauro M.: It turned out that the molecule was toxic per se, and besides FAAH, it could inhibit so many, and affect so many other aspects of the neuronal cells that, of course, it was dangerous.

Seth Adler: Where was the molecule from?

Mauro M.: The study was from Portugal, and was then, the clinical study was run by a company in France. So the general point is that we must accept, and this can be very important for the phytocannabinoids as well, that without basic science, without understanding, we don't have a long way to go.

Mauro M.: So I accept that we can use, in therapy, compounds that are safe, and that show some effects. But if we want to end up with a good molecule for direct pathology, we must do research to understand how it is working. If we believe that we can easily skip those stages, we actually end up with bad surprises that can even kill you.

Seth Adler: Yeah, and it's bad science, is what you said.

Mauro M.: Yeah, right. It's bad science.

Seth Adler: So that's endo, so that's inside. Let's talk about phyto [crosstalk 00:17:27] outside. Let's talk about the plant itself and some of the research that you've done. We talked about osteoporosis. What else can we cover here, as we're discussing your research? Reproductive?

Mauro M.: Yeah, we happened to ... And I must say that, again, the reward, the scientific success was due to the quality of the clinical partners. So we always do biochemistry. And we know how to follow molecules and what they do in the cells. But the ability to show some mechanisms in reproduction, and the neural inflammation was due to the quality of the clinicians who like to join us in doing these investigations.

Mauro M.: So we could show how, again, the FAAH, this hydrolytic enzyme, in peripheral cells of pregnant women, goes down very, very earlier in time, to anticipate spontaneous abortion. It is a condition for which we do not understand the reasons, and we do not have biomarkers to anticipate the clinical symptoms. And-

Seth Adler: I would think that we would have that, based on the fact that that certainly has been happening since the beginning of Man by definition. You would think that the research would be there.

Mauro M.: Yeah, and, you know, what they find it really astonishing is that these lipids seem to really be guardian angel of key mechanisms like reproduction itself. They are controlling very essential biological processes. In this case, they decide whether a new fertilized egg, a blastocyst tissue, as we should say, has to be recognized as a self or non-self by the mother. And I can tell you that, in the very normal healthy conditions, this process is 50% of the time successful, and 50% of the time not. So nature pulls the real strong barrier in deciding who is suitable to go ahead, and who is not. And endocannabinoids out there to supervise, to control that all the processes are correct.

Mauro M.: So, from the very beginning, the implantation, to all the stages that leave this fertilized egg to become a newborn, endocannabinoids have a role. And many, many scientists all over the world have shown how, and through which mechanisms. Which calls for attention in using the plant extracts during pregnancy.

Seth Adler: And what have we found, or what are we thinking as far as that's concerned?

Mauro M.: Well, I can tell you that basic science certainly tells us that, if you activate one of the main target of endogenous compounds, that is called a type one cannabinoid receptor, or CB1, if you activate that, you will end up with an abortion, with the death of the embryo. So if you give something that activates that receptor, and it does chronically, you don't know where you will end. And even if you don't kill the embryo, there are very elegant studies done by others, showing how the entire nervous system is driven by endocannabinoids in the very beginning of the architecture that it has to take. So the neuron, the nervous cell that has to connect to other nervous cell, is driven by endocannabinoids, through receptors. If you now add something that disturbs this equilibrium of the endogenous molecule, you don't know where you will end.

Seth Adler: Understood.

Mauro M.: So this is an arena where you should be really very, very careful.

Seth Adler: How can I, or how can she, strengthen the endocannabinoid system through the plant before pregnancy, if we understand that the CB1 receptor is not to be played with during pregnancy, because we've said a better, or more healthy, endocannabinoid system is going to be better for you in the long run. So what can the plant do to strengthen that ACS beforehand?

Mauro M.: I think this is a very, very difficult question. In the case of reproduction, you know they show this, that even, let's say, the geography of the actions is important, where things happen. So that you need very little endocannabinoids in the place where the embryo has to sit, in the maternal placenta, what they call the implantation side. But next to it, there should be almost no endocannabinoids. But a few centimeters from there, you need high levels to allow a number of other processes that allow the placenta to work properly. So here, we really have a very fine-tuning, whereby I would not say that adding something from a outside, in a high amount, and going everywhere, can be of any benefit.

Seth Adler: So hence the science, hence the research that we're doing, to identify what it is, and where it goes.

Mauro M.: And where it goes. So location is a very real [imageration 00:23:19] that could be true more in general. We have many drugs that are very potent, and very active on the target, but because this endocannabinoid system is ubiquitous, the real problem is that we should find the way to drive the drugs only on the right target, skipping the others, which is not at all easy. But this, I think, the next frontier, the next challenge we have.

Seth Adler: As we saw here, that's exactly where we are, so to speak.

Mauro M.: Exactly.

Seth Adler: Let's go back to degenerative. Anything else besides osteoporosis that you've been working on, that you can share with us as far as conditions?

Mauro M.: Yeah, the other major field where we happen to have some relevant information was for clinicians is the group on neural inflammatory diseases. That means, especially, multiple sclerosis. And more recently Alzheimer disease. So there we could find that the real patient, there are some alterations of the endogenous system that can be specific for the pathology, which is again, a new frontier for research. Because you know that, waiting for good therapeutic targets, many people are looking for biomarker of a disease, and that good biomarkers should appear much earlier than the clinical symptoms, and should be easily accessible, so-

Seth Adler: And identified.

Mauro M.: And identified. So, for neurological diseases, of course you see how difficult it could be to have access to the brain. And what we have been working for years now, is to understand, to prove, how blood cells, specific blood cells, can be mirrors of what happened in the brain. And in this respect, we could show that, in multiple sclerosis, there are certain immune cells that bring similar defects as the central nervous system shows, as the neurons show. And in Alzheimer, other blood cells have a different effect. So if we are able to go ahead in this direction, we should build a group of data big enough to compare different diseases and alterations, and understand if there are selected biomarkers, that may help us to identify much earlier than clinical symptoms, a certain disease.

Seth Adler: Yeah.

Mauro M.: Which is not easy.

Seth Adler: That's not easy, and that's the big news, and that's what to work on. I've spoken with Dr. David Schubert at the Salk Institute, who did some initial work on Alzheimer's, and came away thinking that cannabis. Because, you know, he did not have distinctions at the time, but that cannabis attacked the soft tissue. I don't know if you read his paper, and that it could be, in essence, not a solution for, but certainly a help against Alzheimer's. What are your thoughts, there, based on your own research?

Mauro M.: Well, what we are actually finding in a real patient is that there are early alteration of the endogenous system. And again, when this happens, you can expect that a right amount of the right compounds, coming from a plant, might compensate for that. And in fact, even in this conference, if I think of the lecture by my colleague and friend, Andreas Zimmer, what they found is that, at a certain age, THC can be beneficial for cognitive impairment, because it compensates a decline of the endogenous system. But if you do the same at a different age, which is a young age, you may have a disaster.

Seth Adler: Yes, before 18, forget about it.

Mauro M.: Exactly. So when we understand how, in neural inflammatory diseases, these changes go, we might think of using the right active principles of a cannabis extract to correct or help solution of the disease.

Seth Adler: As per Schubert, Zimmer, and Marricone, right?

Mauro M.: Oh, it would be nice.

Seth Adler: Now, is it the same kind of thinking when we're talking about multiple sclerosis?

Mauro M.: Yeah, multiple sclerosis is a complex disease because it has a number of drivers: partly genetic reasons, part -- quite relevant and not so much understood -- environmental factors. But I think that, at the end, we may end up showing that there are alterations, like the one we found in a specific type of immune cells, in the hydrolase of the [endocannabulose 00:28:09], the FAAH. And maybe the environment can affect this alteration by what is called epigenetic regulation. Not to be technical, but the meaning is that, you don't need to break your message to alter your message, what we have written in any cells to know what to do. It could be enough not to open the right page, and then, if we have something that can open that page, and let us read it, maybe we could solve the problem. So I would not be too surprised if we learn that there are ways through which environmental factors -- food included, physical activity included -- might correct a defect that we are now knowing to be very early in those patients that will unfortunately develop the disease.

Seth Adler: So cannabis, essentially, a tool in the toolbox of keeping people healthy. ECS, the endocannabinoid system. The fact that ... And you heard my friend from the United States say, that when we bring up the endocannabinoid system to physicians in the United States, they simply have no idea. They were not taught about this. Is that the same in Italy? Is it the same worldwide? What are your thoughts on just educating doctors, physicians, in medical school, about the endocannabinoid system?

Mauro M.: Well, I can tell you, you mentioned Canada as a reference for an advanced country. In this respect, they certainly were. When I happen to be the president of the International Cannabinoid Research Society -- that was back in 2010 -- I could also have the [inaudible 00:29:53] lecture to the first course for medical doctor, that in Canada, the association wanted to launch. And think that there's a huge need for education. Medical doctors, usually, do not really know what we are talking about. The situation in Italy is not too bad, in the sense that now we have textbooks for medical students where there is a chapter on endocannabinoids. And I had the pleasure to contribute to some of them.

Seth Adler: There we go.

Mauro M.: And I also noticed that translating some foreign book, like one, I don't know if I can bake the name, but a very famous biochemistry book in U.S., for medical students, where they mention some effects of endocannabinoids in the chapter of the lipids.

Mauro M.: So to make it short, certainly we need to inform much better the student that, first, we have endogenous compounds that are there to work every day, and every moment, to keep our physiology. And that many pathological conditions are linked, in a way or another, to a dis-regulation of our own signals. Then, we have to know that there are some plant extracts that, by acting on our endogenous system, can be potentially very useful. Although that does not mean that the more you get, the better you feel.

Seth Adler: That's not what we want to do. Why were you different? If, worldwide, this is what the case is, as far as it not being taught, and you said you've been working in this since your beginning. How were you made aware of the fact that we have an endocannabinoid system, and that you should actually devote, essentially, your entire career to it.

Mauro M.: Well, this is a nice question, thanks. I can tell, it was, in a way, by accident. Everything started because I was very actively involved, and partly that remained in my own roots, as 'til now, as a researcher, in eicosanoid biochemistry. It might sound a little bit technical, but simply, I was very much involved how, arachidonic acid, one lipid that we need to build from other lipids that we eat. So it is called an essential fatty acid, how it was working to make bioactive compounds that are very, very important for us. If I say, prostate gland, and so leukotriene trienes, maybe everybody thinks of reproduction in a way. And inflammation, allergy, asthma.

Mauro M.: And the one key enzyme for these molecules, that were very well known in the '90s. Actually a Nobel Prize was given for their discovery, 10 years earlier, to Sir Samuelsson. This enzyme, called lipoxygenase, happened to be reported as an enzyme for anandamide, when people looked at anandamide as a particular derivative of arachidonic acid.

Mauro M.: So knowing lipoxygenase, I was curious about this [inaudible 00:33:23] substrate. And starting to work with it, I realized that there was a lot more to understand. It is not a simple derivative of this fatty acid; it's a really new molecule, and from there, we happened to do quite a number of things.

Seth Adler: And I think I only have spoken with Raphael Mechoulam himself about anandamide. So if you could just elucidate -- and that was the word, I think -- on that, so that a general audience can understand.

Mauro M.: You know, in our body, we need signals to let one cell know from another cell that everything is under control, and tat you should do that because I'm doing this. That's how so many different cells can make one organism work improperly, or react improperly, also to the external stimuli. And these messages that they send.

Seth Adler: These are the glasses that are making their way here, by the way. We're here, late night at the conference center, so they're getting them from one place to another. Apologies, go on.

Mauro M.: No problem. So usually, these signals are made of certain organic molecules. And one of the most relevant are the lipids. So what we also eat, like the oil or the fats, we have this type of molecule inside with a very special role, not only to carry energy, or to make us too fat, or too thin. We knew, until the '90s, that the most important lipid signals were made of this fatty acid that we call arachidonic acid. What we learned after Raphael Mechoulam work is that adding a little molecule to this fatty acid, you could generate a new group of molecule with a completely different way of being active. Different target to deliver the message. Different molecules to keep their levels, to synthesize them or break them down. These are the endocannabinoids. The name comes after the fact that plant extract, cannabis extracts, were discovered first, as the active molecules. So the first target that were found in our body were called cannabinoid receptor. But actually, they're not there for the cannabis extract; they're there for our endogenous molecule, the endocannabinoids.

Mauro M.: So we have many, but certainly the two that are more relevant are a little ... I should say, technically, biochemically speaking, is an amide of arachidonic acid that we call anandamide, not the chemical name, but the name after the Sanskrit word "ananda" for inner bliss. And the other one is 2AG. This is a chemical name. If I say, is a little bit nasty if you want, is a two arachidonide glycerol. But 2AG and anandamide remain the two most relevant endogenous compound that are doing so many things in our body.

Seth Adler: So that brings us back to the kind of adding the molecule, and right on the doorstep of FAAH, again. And I want to zero in on the molecule that was added, with terminal results. What was the molecule? You said it was from Portugal and ...

Mauro M.: You know, it has a, not commercial ... It's short name is Bial with a number after that, stand and something. And it does inhibit the FAAH at the very high.

Seth Adler: What substance was it.

Mauro M.: Oh, it's just chemical.

Seth Adler: It was just a chemical.

Mauro M.: Just chemically synthesized.

Seth Adler: A synthesized chemical.

Mauro M.: Yeah, yeah, yeah. Nothing natural. It has nothing to do with nature.

Seth Adler: Interesting.

Mauro M.: It was made in the lab with the aim of blocking that enzyme.

Seth Adler: And so I might be kind of outside of your purview when I ask you the next question, which is, we are starting to talk about synthesized cannabis. And I know that there's already synthesized cannabis out there, and synthesized cannabinoids and such. But please answer me as a scientist, why would we synthesize these cannabinoids if we can have them naturally?

Mauro M.: There could be different reasons. In general, when you launch a drug development program, it's because you want to start from a scaffold that nature delivers, and you want to make it better. Better can mean either more active on your target, or more selective towards the target. For instance, the famous THC, delta-nine tetrahydrocannabinol, it is active on the type one cannabinoid receptors, CB1, but also on type two cannabinoid receptor. If you want to take only conditions where CB1 is involved, you are not happy enough with the molecule that can bind also elsewhere.

Seth Adler: Understood.

Mauro M.: And so you try to develop something, starting from the example that nature gave you, that scaffold, to make a very specific ligant, so agent able to bind to the target you want.

Seth Adler: Yeah, when we hear the results for Marinol, which is synthesized cannabis. I don't know how much you know about them. I'm asking you a lot of different things here. I understand. And we haven't had such great results, and we've had side effects, which are different than the side effects which we see from cannabis, which are, you might get a little tired, and you might be a little paranoid, you might get a little hungry, not tired. And there are others. I simplify. But we saw some really negative effects from Marinol. And that was synthesized medicine. So someone that is obviously for the plant here.

Mauro M.: Well, let's say, there are many, many things in your question that is, of course, interesting. But let's say, if you want to make a kind of reference schema for who is listening to us, there could be reasoning synthesizing in the lab, exactly the same molecule that you have in nature. Just because it is simple. It's simpler to have it, all the amounts you need, without going to plants, and then go through a long extraction procedure.

Seth Adler: Understood.

Mauro M.: And so that's easy. But it can be dangerous because what we are understanding, in the context of the cannabinoid signaling, is that there is this entourage effect. So how a certain environment of molecules can affect the activity of the main molecule, and how adding around a certain composition, a certain cocktail, can modify your activity. Which means, I can identify the active principle, but maybe, when I put it out of context, or I just make it pure, the final results will not be the same.

Seth Adler: Interesting, which makes your, and your colleagues', work all the more difficult, because we said we don't want to paint with a broad brush just all over the place, but we do want to respect what we are calling the entourage effect, to make sure that we don't oversimplify into danger.

Mauro M.: Exactly. So once again, these type of molecules is extremely powerful, and I believe that it really holds hopes for future therapeutics. But we cannot be so superficial to think that it's just a matter of using a cocktail by accident. We have to understand what is behind to do science, and by accompanying a clinical application with science, scientific knowledge, we will end up with solutions. Otherwise, we might have disasters.

Seth Adler: Right, yeah. So we got the work to do. We got to do work.

Mauro M.: Exactly.

Seth Adler: And we can't just shortcut it either.

Mauro M.: Yeah.

Seth Adler: Right? We can't just shortcut it on just as, you know, smoking a joint, so to speak. Or shortcut it and just slice and dice the molecules how you shove it out the door in a pill.

Mauro M.: Exactly.

Seth Adler: It's somewhere in between.

Mauro M.: Shortcuts are only short.

Seth Adler: There we go.

Mauro M.: They're almost never kind of miracles that you by accident find the easy solution and the fast solution.

Seth Adler: There we go. All right, so the last, before the three final questions: So we had some debate at certain points, as you will, with a bunch of scientists, and there were some other folks as well. There was representation from the government, and then there were some other players as well, it seemed. And at certain points, folks really thought that they knew what they were talking about, and were very vociferous. And I'm pretty good at balancing it out. But I did notice, when I chose not to use the microphone, if there was someone that was able to calm down the room, it was you. And you mentioned your history of connecting -- and I know that you were talking about scientifically -- but as far as humanity is concerned, are you aware that you have this ability? And if you're not, where might it be from?

Mauro M.: I thank you. I think it's always nice to learn that there is a positive attitude, and you're correct. No, maybe one thing that can have is due to my profession as a teacher. I have to not only try to explain what I want to transfer to the students, but also to see if they receiving. And if they are not, find the way that they can circumvent the program. Otherwise, I would teach to myself, which is really pointless.

Seth Adler: It really is.

Mauro M.: Yeah, yeah. And, on the other hand, I hope that having the attitude to say something based on quite heavy daily routine of working on those things will gain attention by the ones who are attending. And then, they like to receive what you're saying, but again, I also want to be open to listen to what the others are saying.

Seth Adler: There we go. It's "I've done the work, let me explain the work that I've done." And also, "I have one mouth and two ears. Let me listen".

Mauro M.: You said it right, which is always very important.

Seth Adler: All right. That's good advice for anybody.

Mauro M.: And if I may add, I don't know if we mentioned that, we have such an example in someone like Professor Mechoulam, who could really say to everybody they'll want to listen to you, but is instead always there, ready to ...

Seth Adler: To listen.

Mauro M.: ... to listen.

Seth Adler: Sitting in the front row, literally just taking it all in, and exactly. If there was ever a room where he could just say, "You know what? This is the way it is." He could certainly do that, but he does not. That's not his approach at all.

Seth Adler: Okay, so three final questions. I'll tell you what they are. I'll ask you them in order. What has most surprised you in cannabis? I cannot wait for you to tell me that. What has most surprised you in life? And on the soundtrack of your life, one track, one song, that's got to be on there. But first things first. What has most surprised you in cannabis?

Mauro M.: Such a wealth of potentialities in the compounds it has. Which is a big challenge. If we are able to decipher what is inside, instead of doing so many chemical syntheses that, I don't know if you are aware of the process, but now they go even in silico. Which means that, before making the molecules, you can model, handwritten, thousands of different [variabilities 00:45:40]. Why, instead of doing that at the computer, and then, by chemical synthesis, there are plans that have the old bunch of possibilities there, ready. And we should be able to understand how to take advantage of each of these precious ingredients. So I was surprised that, in nature, you could find such a wealth of possibilities, such an array of different chemical solutions to-

Seth Adler: And it sounds like we're not even ... Are we even at the starting line, as far as understanding all of it?

Mauro M.: Right, right. And on the other hand, this is also expected, maybe not in that extent that we are understanding now, but when we think of folklore medicine, or traditions that, in our population, and in each country, can be different, but it is always there. By using, by observing, by paying attention, once again, to what nature could give you, you could solve certain pathologies. Of course, you understand that there are many drugs already there for us to use.

Seth Adler: As far as just a culture, and society and the way "ancient medicines" so to speak, in quotation marks, do you have thoughts around ... I know the word we were using was recreational in that room, but I mean adult use. Meaning wellness, meaning actually smoking that joint as just a, instead of having a glass of wine, this is what I'm doing. Do you have thoughts around that or?

Mauro M.: Well, I can tell you, here I would have not a prohibitionist position, but a more strict position. I mean, would love, I would dream that each of us finds his own way, and the ability to relax after a stressing day without any need of any external thing.

Seth Adler: Aha! You know what? That's, it's not prohibitionist, it's purist. I like that. We should understand our body enough that we can do this without any help.

Mauro M.: Absolutely. Because I think that then, at first, you really enjoy any pleasure you may have additional. And you have the strength, the thickness, to treat it as a pleasure.

Seth Adler: There we go.

Mauro M.: And never become dependent on it.

Seth Adler: Yes, of course.

Mauro M.: Because otherwise, we could go in a path that could be dangerous. So we let them choose if it's better a joint or a glass of vodka or whatever. But that is not the way that we should-

Seth Adler: Don't think about it that way.

Mauro M.: ... think about in our [inaudible 00:48:34]. That would be my overall position.

Seth Adler: I love it. I love that position. I appreciate that. What's most surprised you in life?

Mauro M.: This is a different question, actually.

Seth Adler: Yes, of course.

Mauro M.: But, you know, I have two children, and they're still teenagers, but they're growing. I think that, when you have this luck, or at least you can appreciate other children around you, you understand that you have a certain obligations that go beyond you. So I have an attitude so that you might leave a world that is at least as reasonable as the one you received should be.

Seth Adler: Interesting. That's not usually where that answer goes. I hope that everyone with children -- and without children-

Mauro M.: And without children.

Seth Adler: ... tries to really accomplish that goal. Because we might be in a better place.

Mauro M.: Yeah, much better place.

Seth Adler: Yeah, if that was the case.

Mauro M.: Again, a way of putting the references of your actions and the way you interpret your life.

Seth Adler: Yeah.

Mauro M.: In a slightly wider context.

Seth Adler: You do. So you have a bigger picture point of view, it sounds like. Is that simply because you're a scientist? Or is your brain informed by your mother and father? Why do you think you look at things in such a big way? When I say, "Should we do this, or this?" You say, "Well, have you considered this?" Which is a much bigger picture view. How do you have that?

Mauro M.: Well, I can say that, to me, my parents were certainly a fantastic example. And my mother is still alive and, in her old age, she is still a great example. And by things that happen in life, I used to move from one city to another with my family when I was a child. So I don't know if that had a lot to be-

Seth Adler: Get out there.

Mauro M.: ... as open. So I feel every city where I lived as my own city. So I still have very strong contacts and feelings, and I appreciate everyplace where I was. It was not the feeling of moving from an unknown place to another. Just a [inaudible 00:50:54] keeping something every time.

Seth Adler: That's interesting.

Mauro M.: And even if it was far away abroad from Italy.

Seth Adler: If Rome is home, so to speak, what would be a second city? You saying that you've taken from everything, but just so we get a context.

Mauro M.: And you're right, because the second city, it embarrasses me a little bit, because I would have at least three candidates immediately, two in Italy and one abroad. But if I have to say the one that gave me most in my education, certainly in Utrecht, in the Netherlands, where I spent a few years. I actually used to work at university, there, at the faculty of chemistry. For other reasons, for my young age, was Bologna, that you might know. It was one of the very first, or maybe they say the first university in the world ever, is in the middle north of Italy. And I spent there almost 10 years.

Mauro M.: And then, a small city, not too far from where I live now, it is called Teramo, where I was appointed, I got, there, my first chair in biochemistry. And I could work really very, very well, with many people, making many new things. So, let's say I would have three candidates.

Seth Adler: All right, so very simply. On the soundtrack of your life, one track, or one song that must be on there. So this is a song that's either come with you throughout, or one that's especially specific and special to you.

Mauro M.: A nice question that ...

Seth Adler: Don't think about it often, I would imagine.

Mauro M.: Yeah, too much. When I think too much, then it's already bad, I would say. I have in mind the motif, maybe I'm not so ... When I met my wife, we had this song, I think every couple does. That was played by an Italian singer, Ramazzotti. And I cannot remember; if my wife will ever know that, she will kill me. But I can't remember the name, I know the ... But let's say it was a kind of romantic, not too romantic, but romantic enough.

Seth Adler: Who, this is the composer or the singer?

Mauro M.: The singer is Ramazzotti.

Seth Adler: Ramazzotti.

Mauro M.: And he used to be very famous. And he also had some duet with famous American singers. But again, I should think about the name. But anyway ...

Seth Adler: Listen, you've demonstrated, Mauro, that there is enough going on in the mind that it is okay if you can't recall everything at every moment.

Mauro M.: Let's put it this way, right.

Seth Adler: Yes, of course. I mean, essentially, some of you has been to outer space. Let's keep that in mind.

Seth Adler: Mauro Marricone. I thank you so much for your time.

Mauro M.: Thank you so much for interview. It was a pleasure.

Seth Adler: And there you have Dr. Mauro Marricone. Very much appreciate his time. Very much appreciate your time. Stay tuned.

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